Cell-type identification using multi-modal machine learning

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Solution Overview

Problem

Current methods for cell-type assignment in single-cell transcriptomics data are limited by reliance on predefined markers, manual curation, high computational intensity, and limited interpretability, with existing approaches failing to provide reliable and interpretable results.

Innovation Solution

A machine-learning-based method using multi-modal sequencing platforms to identify a compact panel of predictive genes by correlating mRNA and protein expression data, allowing for accurate cell-type classification without relying on clustering analysis or bulk RNA sequencing data.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If immunostaining techniques with surface marker proteins are used for cell-type assignment, then measurement precision is improved, but productivity deteriorates due to low throughput

Engineering Contradiction:
Improvecell-type assignment accuracyVSAvoidthroughput
Core Design Contradiction:
Measurement precisionVSProductivity

Solution Approach 1:

The patent replaces the mechanical/chemical immunostaining process with a computational machine learning model that processes scRNA-seq data. The model uses gene expression profiles to predict cell types, substituting the physical antibody-based detection system with an information-processing system that achieves comparable or superior accuracy while enabling high-throughput analysis of thousands of cells simultaneously.

Inventive Principle:
Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent creates a computational model that learns from training data containing paired scRNA-seq and immunostaining results. The model copies the cell-type classification capability from the gold standard immunostaining method into a predictive algorithm, allowing it to replicate accurate cell-type assignment without requiring actual protein staining for each cell.

Inventive Principle:
Principle #26Copying

2Productivity

If machine learning models trained on bulk RNA-seq data are used, then productivity is improved, but reliability deteriorates due to limited generalizability

Engineering Contradiction:
Improveprocessing speedVSAvoidgeneralizability
Core Design Contradiction:
ProductivityVSReliability

Solution Approach 1:

The patent changes the fundamental parameter of training data granularity from bulk RNA-seq (population-level averages) to single-cell RNA-seq (individual cell-level data). This parameter change enables the model to learn cell-type-specific expression patterns and variability, significantly improving generalizability to new single-cell datasets while maintaining efficient processing through automated machine learning pipelines.

Inventive Principle:
Principle #35Parameter changes

3Measurement precision

If reference data set methods are used for cell-type assignment, then measurement precision is improved, but device complexity increases due to computational intensity

Engineering Contradiction:
Improvecell-type assignment accuracyVSAvoidcomputational complexity
Core Design Contradiction:
Measurement precisionVSDevice complexity

Solution Approach 1:

The patent performs preliminary action by pre-training the machine learning model on a comprehensive reference dataset containing paired scRNA-seq and immunostaining data from multiple cell types. This pre-training phase captures general cell-type expression patterns and variability, enabling the model to achieve high accuracy on new datasets with minimal additional computational resources, thus reducing the complexity burden on end users.

Inventive Principle:
Principle #10Preliminary action

Solution Approach 2:

The patent implements a dynamic two-stage approach where the model adapts its behavior based on input data characteristics. The system can operate in a fast prediction mode for routine analysis or switch to a more computationally intensive refinement mode when higher precision is needed, allowing flexible resource allocation that balances accuracy requirements against available computational resources.

Inventive Principle:
Principle #15Dynamics

4Ease of operation

If predefined marker panels are used for cell-type assignment, then ease of operation is improved, but reliability deteriorates due to limited interpretability

Engineering Contradiction:
Improvesimplicity of useVSAvoidinterpretability
Core Design Contradiction:
Ease of operationVSReliability

Solution Approach 1:

The patent incorporates feedback mechanisms that provide interpretable insights into model predictions. The system analyzes and reports which genes and expression patterns most strongly influenced each cell-type prediction, giving users feedback about the biological rationale behind classifications. This maintains ease of operation while significantly improving interpretability compared to black-box approaches.

Inventive Principle:
Principle #23Feedback

Data Source

PatentUS20230317204A1Cell-type identification
Publication Date: 2023.10.05 F HOFFMANN LA ROCHE INC
  • US20230317204A1 patent drawing
  • US20230317204A1 patent drawing
  • US20230317204A1 patent drawing

AI summary

The present invention provides a method comprising (a) obtaining a single cell gene expression profile comprising gene expression measurements for a set of genes, for a plurality of cells, and a single cell protein expression profile comprising protein expression measurements for two or more proteins, for the plurality of cells; (b) using the single cell protein expression profiles and an unsupervised learning method to assign a cell type class to at least some of the plurality of cells; and(d) applying a feature selection process to the single gene expression profiles to identify genes in the single cell gene expression profiles that are predictive of the cell type classes assigned in step (b), wherein the genes identified in step (d) form a predictor set of genes for predicting the cell type of one or more cells.